Integrated Transcriptomic and Metabolomic Analysis Reveals the Antibacterial Mechanisms of the Novel Peptide FxCy2 against Helicobacter pylori

Antibiotic resistance and gut microbiota dysbiosis have become major challenges to Helicobacter pylori eradication therapy. Antimicrobial peptides (AMPs) are promising alternatives due to multifaceted mechanisms and reduced side effects. In the previous study, we obtained a novel AMP, FxCy2, from the fermentation product of Lactobacillus paracasei, which exhibited strong inhibitory activity against H. pylori. This study further investigates the underlying anti-H. pylori mechanisms by combining transcriptomics and metabolomics. FxCy2 disrupted membrane integrity, increased permeability, and induced intracellular leakage. Multiomics analyses revealed disruption of oxidative phosphorylation, amino acid metabolism, and nucleotide biosynthesis, impairing energy metabolism and membrane formation. Furthermore, FxCy2 exhibited antivirulence potential, evidenced by reduced urease activity, transcriptomic indications of altered secretion- and adhesion-related functions, and docking-suggested interactions with key virulence-associated proteins. Overall, these findings provide novel insights into the anti-H. pylori mechanisms of FxCy2 and support its potential as a sustainable, nonantibiotic therapeutic strategy for H. pylori-associated infections.